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Exploration of the rare variant germline genomic architecture of sarcoma
No full textSarcoma is a rare cancer occurring in tissues of mesenchymal origin, constituting ~1% of cancer diagnoses and comprising >70 subtypes. On account of its low frequency, sarcoma susceptibility studies to-date have had limited power for new susceptibility gene identification. This thesis presents analyses relating to genetic susceptibility to sarcoma.
I performed case-control gene-burden analyses integrating data from six sarcoma case datasets and four control datasets, which I organised into four analysis “pillars”. I initially focussed on 91 established cancer susceptibility genes, followed by exome-wide analyses with two variant filtering “tiers” (Tier 1: loss-of-function variants and Tier 2: loss-of-function and protein-altering variants). I combined the results from three analysis pillars (comprising 3,569 cases and 21,788 controls in total) through random effects meta-analysis. Despite being better-powered than previous studies, with ~80% to detect a hypothetical novel sarcoma susceptibility with odds ratio of ≥5 down to a population frequency of deleterious variants of ≥0.17%, no statistically-significant novel gene-sarcoma risk associations were identified. However, association signal for TP53, a well-established sarcoma susceptibility gene, was “reidentified” in the cancer susceptibility gene analyses and subsets of the exome-wide Tier 2 analyses.
The identification through clinical testing of pathogenic variants in established cancer susceptibility genes can enable implementation of enhanced screening, risk-reduction interventions and identification of other “at-risk” relatives through familial cascade testing. There is thus substantial potential clinical value in extending the repertoire of cancer susceptibility genes. However, no novel sarcoma susceptibility genes were identified through these analyses. The size of the analysis and accordant power therefore imply that pathogenic variants in hereto undiscovered sarcoma susceptibility genes are likely associated with small effect size and/or occur at low frequency and/or association is limited to specific rare subtypes, meaning their clinical utility may arguably be quite limited
Radical resection of large metastatic non-functioning pancreatic neuroendocrine carcinoma complicated by splenic vein thrombosis and sinistral portal hypertension.
No full textINTRODUCTION AND IMPORTANCE: There are limited reports in the literature of radical surgical resection for pancreatic neuroendocrine carcinoma (PNEC). In patients with non-functioning PNEC (NF-PNEC) within the tail of the pancreas tumours can cause splenic vein thrombosis (SVT) and subsequent sinitral portal hypertension (SPH). Radical surgical resection in such patients with concomitant liver metastasis has not previously been reported. CASE PRESENTATION: We present a 67-year old female patient who presented with a large NF-PNEC within the tail of the pancreas with liver metastasis. We performed a distal pancreatectomy, splenectomy, partial gastrectomy and liver resection to achieve radical resecton. DISCUSSION: All patients with NF-PNEC within the tail of the pancreatic should be considered for radical surgical resection. In the presence of multi-visceral involvement and complications such as SVT and/or SPH multi-speciality surgical expertise is likely to be required. CONCLUSION: Radical multi-visceral resection for large NF-PNEC can be safely performed in the presence of SVT and SPH
Biocompatibility characterisation of CMOS-based Lab-on-Chip electrochemical sensors for in vitro cancer cell culture applications.
No full textLab-on-Chip electrochemical sensors, such as Ion-Sensitive Field-Effect Transistors (ISFETs), are being developed for use in point-of-care diagnostics, such as pH detection of tumour microenvironments, due to their integration with standard Complementary Metal Oxide Semiconductor (CMOS) technology. With this approach, the passivation of the CMOS process is used as a sensing layer to minimise post-processing, and Silicon Nitride (Si3N4) is the most common material at the microchip surface. ISFETs have the potential to be used for cell-based assays however, there is a poor understanding of the biocompatibility of microchip surfaces. Here, we quantitatively evaluated cell adhesion, morphogenesis, proliferation and mechano-responsiveness of both normal and cancer cells cultured on a Si3N4, sensor surface. We demonstrate that both normal and cancer cell adhesion decreased on Si3N4. Activation of the mechano-responsive transcription regulators, YAP/TAZ, are significantly decreased in cancer cells on Si3N4 in comparison to standard cell culture plastic, whilst proliferation marker, Ki67, expression markedly increased. Non-tumorigenic cells on chip showed less sensitivity to culture on Si3N4 than cancer cells. Treatment with extracellular matrix components increased cell adhesion in normal and cancer cell cultures, surpassing the adhesiveness of plastic alone. Moreover, poly-l-ornithine and laminin treatment restored YAP/TAZ levels in both non-tumorigenic and cancer cells to levels comparable to those observed on plastic. Thus, engineering the electrochemical sensor surface with treatments will provide a more physiologically relevant environment for future cell-based assay development on chip
Immunogenic cell death in cancer therapy
No full textTriple negative breast cancer (TNBC) is a heterogenous disease which carries a poor prognosis, with the worst outcomes in the basal-like subtype. Despite the introduction of immunotherapy in the treatment paradigm the response rates are modest, especially in advanced disease. There remains an unmet clinical need for novel treatment approaches to improve tumour-specific immune responses for disease control. Conventional cancer treatments cause cell death and the mechanism of this death can determine anti-cancer immunity. The main aim of this thesis was to understand how treatment mediated cell death could be manipulated to engage TNF-mediated death receptor signalling to promote a more immunogenic cell death in this breast cancer subtype.
To understand tumour immune responses an immune-competent in vivo model was required. To this end, organoid models were derived from spontaneously forming mammary tumours in genetically engineered (GEMM) BLG-Cre;Brca1f/f;p53+/- mice. These could be reimplanted in syngeneic mice and formed organoid derived tumours that reflected the heterogeneous primary tumours with human basal-like features. To complement this model, and address the clinical validity of murine experiments, I also developed techniques to measure the modality of cell death in human TNBC Patient Derived Organoids (PDOs) from the BCN Organoid Facility.
I have shown that GEMM BLG-Cre;Brca1f/f;p53+/- organoids have necroptotic machinery and that the combination of IAP antagonists and caspase inhibition can drive TNF-mediated necroptotic cell death. In immune infiltrated tumours this can enhance immune checkpoint inhibitor (ICI) responses. Furthermore, in organoid derived tumours with an increased interferon gene signature, the addition of STING agonism in vivo sensitises tumours to necroptosis.
In most human TNBC models RIPK3 is absent and chemotherapy causes apoptotic cell death. Releasing the break on RIPK1, using IAP antagonists, can further drive cell death in PDOs treated with chemotherapy, PARP inhibition and novel antagonists of anti-apoptotic BH3 family proteins. Furthermore, engaging the IFN pathway can induce RIPK1 mediated death which may be more immunogenic. Overall, this work suggests that engaging RIPK1 signalling using novel drug combinations may be a promising strategy to harness the potential for therapy induced immunogenic cell death and anti-tumour immune responses
A deep-learning framework to predict cancer treatment response from histopathology images through imputed transcriptomics.
No full textAdvances in artificial intelligence have paved the way for leveraging hematoxylin and eosin-stained tumor slides for precision oncology. We present ENLIGHT-DeepPT, an indirect two-step approach consisting of (1) DeepPT, a deep-learning framework that predicts genome-wide tumor mRNA expression from slides, and (2) ENLIGHT, which predicts response to targeted and immune therapies from the inferred expression values. We show that DeepPT successfully predicts transcriptomics in all 16 The Cancer Genome Atlas cohorts tested and generalizes well to two independent datasets. ENLIGHT-DeepPT successfully predicts true responders in five independent patient cohorts involving four different treatments spanning six cancer types, with an overall odds ratio of 2.28 and a 39.5% increased response rate among predicted responders versus the baseline rate. Notably, its prediction accuracy, obtained without any training on the treatment data, is comparable to that achieved by directly predicting the response from the images, which requires specific training on the treatment evaluation cohorts
"Tell me what is 'better'!" How medical students experience feedback, through the lens of self-regulatory learning.
No full textINTRODUCTION: While feedback aims to support learning, students frequently struggle to use it. In studying feedback responses there is a gap in explaining them in relation to learning theory. This study explores how feedback experiences influence medical students' self-regulation of learning. METHODS: Final-year medical students across three campuses (Ireland, Bahrain and Malaysia) were invited to share experiences of feedback in individual semi-structured interviews. The data were thematically analysed and explored through the lens of self-regulatory learning theory (SRL). RESULTS: Feedback interacts with learners' knowledge and beliefs about themselves and about learning. They use feedback to change both their cognitive and behavioural learning strategies, but how they choose which feedback to implement is complex. They struggle to generate learning strategies and expect teachers to make sense of the "how" in addition to the "what"" in planning future learning. Even when not actioned, learners spend time with feedback and it influences future learning. CONCLUSION: By exploring our findings through the lens of self-regulation learning, we advance conceptual understanding of feedback responses. Learners' ability to generate "next steps" may be overestimated. When feedback causes negative emotions, energy is diverted from learning to processing distress. Perceived non-implementation of feedback should not be confused with ignoring it; feedback that is not actioned often impacts learning
Pembrolizumab versus methotrexate, docetaxel, or cetuximab in recurrent or metastatic head and neck squamous cell carcinoma (KEYNOTE-040): Subgroup analysis by pattern of disease recurrence.
No full textBACKGROUND: In the phase 3 KEYNOTE-040 study, pembrolizumab prolonged OS versus chemotherapy in previously treated recurrent or metastatic (R/M) HNSCC. We present a post hoc subgroup analysis by disease recurrence pattern: recurrent-only, recurrent and metastatic (recurrent-metastatic), and metastatic-only HNSCC. MATERIALS AND METHODS: Patients had HNSCC that progressed during or after platinum-containing treatment for R/M disease or had recurrence or progression within 3-6 months of previous platinum-containing definitive therapy for locally advanced disease. Patients were randomly assigned (1:1) to pembrolizumab 200 mg Q3W or investigator's choice of standards of care (SOC): methotrexate, docetaxel, or cetuximab. Outcomes included OS, PFS, ORR, and DOR. The data cutoff was May 15, 2017. RESULTS: There were 125 patients (pembrolizumab, 53; SOC, 72) in the recurrent-only subgroup, 204 in the recurrent-metastatic subgroup (pembrolizumab, 108; SOC, 96), and 166 in the metastatic-only subgroup (pembrolizumab, 86; SOC, 80). The hazard ratio (95% CI) for death for pembrolizumab versus SOC was 0.83 (0.55-1.25) in the recurrent-only, 0.78 (0.58-1.06) in the recurrent-metastatic, and 0.74 (0.52-1.05) in the metastatic-only subgroups. PFS was similar between treatment arms in all subgroups. ORR was 22.6% for pembrolizumab versus 16.7% for SOC in the recurrent-only, 10.2% versus 6.3% in the recurrent-metastatic, and 15.1% versus 8.8% in the metastatic-only subgroups. DOR was numerically longer with pembrolizumab in all subgroups. CONCLUSION: Pembrolizumab provided numerically longer OS and durable responses in all subgroups compared with SOC, suggesting that patients with previously treated R/M HNSCC benefit from pembrolizumab regardless of recurrence pattern
Adult brain tumour research in 2024: Status, challenges and recommendations.
No full textIn 2015, a groundswell of brain tumour patient, carer and charity activism compelled the UK Minister for Life Sciences to form a brain tumour research task and finish group. This resulted, in 2018, with the UK government pledging £20m of funding, to be paralleled with £25m from Cancer Research UK, specifically for neuro-oncology research over the subsequent 5 years. Herein, we review if and how the adult brain tumour research landscape in the United Kingdom has changed over that time and what challenges and bottlenecks remain. We have identified seven universal brain tumour research priorities and three cross-cutting themes, which span the research spectrum from bench to bedside and back again. We discuss the status, challenges and recommendations for each one, specific to the United Kingdom
Magnetic resonance image-guided adaptive radiotherapy enables safe CTV-to-PTV margin reduction in prostate cancer: a cine MRI motion study.
No full textINTRODUCTION: We aimed to establish if stereotactic body radiotherapy to the prostate can be delivered safely using reduced clinical target volume (CTV) to planning target volume (PTV) margins on the 1.5T MR-Linac (MRL) (Elekta, Stockholm, Sweden), in the absence of gating. METHODS: Cine images taken in 3 orthogonal planes during the delivery of prostate SBRT with 36.25 Gray (Gy) in 5 fractions on the MRL were analysed. Using the data from 20 patients, the percentage of radiotherapy (RT) delivery time where the prostate position moved beyond 1, 2, 3, 4 and 5 mm in the left-right (LR), superior-inferior (SI), anterior-posterior (AP) and any direction was calculated. RESULTS: The prostate moved less than 3 mm in any direction for 90% of the monitoring period in 95% of patients. On a per-fraction basis, 93% of fractions displayed motion in all directions within 3 mm for 90% of the fraction delivery time. Recurring motion patterns were observed showing that the prostate moved with shallow drift (most common), transient excursions and persistent excursions during treatment. CONCLUSION: A 3 mm CTV-PTV margin is safe to use for the treatment of 5 fraction prostate SBRT on the MRL, without gating. In the context of gating this work suggests that treatment time will not be extensively lengthened when an appropriate gating window is applied
Chemotherapy and gene expression profiling in older early luminal breast cancer patients: An International Society of Geriatric Oncology systematic review.
No full textBACKGROUND: The benefit of chemotherapy for older patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative early breast cancer (EBC) is a key area of debate. Gene expression profiling (GEP) may identify patients deriving benefit, but their predictive role has not been established for older adults. We summarise evidence on efficacy, safety, and quality-of-life impacts of chemotherapy and on GEP use and impact in older HR-positive, HER2-negative EBC patients. METHODS: We conducted a literature search of PubMed and Embase on publications describing prospective studies evaluating chemotherapy in older adults with HR-positive, HER2-negative EBC and on publications describing retrospective and prospective studies evaluating GEP in older adults. RESULTS: Eight publications on chemotherapy use, including 2,035 older patients with EBC were selected. Only one trial evaluated chemotherapy survival benefits in older adults, showing no benefit. Of four studies comparing different regimens, only one showed the superiority of taxanes versus anthracyclines alone. Those investigating alternative regimens did not show improvements over standard regimens despite significant limitations. Five publications on GEP, including 445,323 older patients, were included and investigated Oncotype DX. Limited evidence shows that GEP aids treatment decisions in this population. GEP was offered less frequently to older versus younger patients. Higher Recurrence Score was prognostic for distant recurrence, but chemotherapy did not improve prognosis. CONCLUSIONS: In older patients with HR-positive, HER2-negative, chemotherapy survival benefits EBC are unclear and GEP is less used. Although its prognostic role is well established, its predictive role remains unknown